US3056809A - Method for introducing an oxygen function into a steroid molecule containing an enol group and compounds thereof - Google Patents
Method for introducing an oxygen function into a steroid molecule containing an enol group and compounds thereof Download PDFInfo
- Publication number
- US3056809A US3056809A US66941A US6694160A US3056809A US 3056809 A US3056809 A US 3056809A US 66941 A US66941 A US 66941A US 6694160 A US6694160 A US 6694160A US 3056809 A US3056809 A US 3056809A
- Authority
- US
- United States
- Prior art keywords
- group
- oxygen
- solution
- hydroperoxy
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims description 47
- 238000000034 method Methods 0.000 title claims description 37
- 150000003431 steroids Chemical class 0.000 title claims description 32
- 150000001875 compounds Chemical class 0.000 title description 12
- 125000002587 enol group Chemical group 0.000 title description 7
- -1 HYDROXY GROUP Chemical group 0.000 claims description 23
- 230000008569 process Effects 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 150000002085 enols Chemical group 0.000 claims description 9
- 238000000354 decomposition reaction Methods 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 229910001882 dioxygen Inorganic materials 0.000 claims description 3
- 230000002269 spontaneous effect Effects 0.000 claims description 2
- 150000001721 carbon Chemical class 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000001301 oxygen Substances 0.000 description 28
- 229910052760 oxygen Inorganic materials 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 238000002425 crystallisation Methods 0.000 description 24
- 239000007787 solid Substances 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 238000006213 oxygenation reaction Methods 0.000 description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 229910052700 potassium Inorganic materials 0.000 description 11
- 239000011591 potassium Substances 0.000 description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 125000001867 hydroperoxy group Chemical group [*]OO[H] 0.000 description 10
- 229910052725 zinc Inorganic materials 0.000 description 10
- 239000011701 zinc Substances 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 229930194542 Keto Natural products 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 150000004703 alkoxides Chemical class 0.000 description 6
- 125000000468 ketone group Chemical group 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Natural products C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229960003387 progesterone Drugs 0.000 description 4
- 239000000186 progesterone Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- UVLDESQWQRMYKD-UHFFFAOYSA-N Neobotogenin Natural products CC1C(C2(C(=O)CC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 UVLDESQWQRMYKD-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- PESKGJQREUXSRR-UXIWKSIVSA-N 5alpha-cholestan-3-one Chemical compound C([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 PESKGJQREUXSRR-UXIWKSIVSA-N 0.000 description 2
- PESKGJQREUXSRR-UHFFFAOYSA-N 5beta-cholestanone Natural products C1CC2CC(=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 PESKGJQREUXSRR-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QOLRLLFJMZLYQJ-LOBDNJQFSA-N Hecogenin Chemical compound O([C@@H]1[C@@H]([C@]2(C(=O)C[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 QOLRLLFJMZLYQJ-LOBDNJQFSA-N 0.000 description 2
- OXLGJTRVVNGJRK-UHFFFAOYSA-N Hecogenin Natural products CC1CCC2(CC3CC4C5CCC6CC(O)CCC6(C)C5CC(=O)C4(C)C3C2C)OC1 OXLGJTRVVNGJRK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-M hydroperoxide group Chemical group [O-]O MHAJPDPJQMAIIY-UHFFFAOYSA-M 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001706 oxygenating effect Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000001072 progestational effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VUXXCVWHUXQPFJ-UHFFFAOYSA-N 1-methylsulfanyl-4-methylsulfinyl-6,7-dihydro-5h-cyclopenta[d]pyridazine Chemical compound CSC1=NN=C(S(C)=O)C2=C1CCC2 VUXXCVWHUXQPFJ-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- JVYYINJWLIGZGB-UHFFFAOYSA-N 4,4,10,13,14-pentamethyl-17-(6-methylheptan-2-yl)-1,2,5,6,7,11,12,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical compound CC12CCC(=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(C)CCCC(C)C)CCC21C JVYYINJWLIGZGB-UHFFFAOYSA-N 0.000 description 1
- JWMFYGXQPXQEEM-NUNROCCHSA-N 5β-pregnane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-NUNROCCHSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- 229930183217 Genin Natural products 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241001342522 Vampyrum spectrum Species 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000001441 androstanes Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001829 cholanes Chemical class 0.000 description 1
- 150000001838 cholestanes Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 150000002133 ergostanes Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- UVLDESQWQRMYKD-MOAZMYQBSA-N gentrogenin Chemical compound O([C@@H]1[C@@H]([C@]2(C(=O)C[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 UVLDESQWQRMYKD-MOAZMYQBSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002432 hydroperoxides Chemical group 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 150000003124 pregnadienes Chemical class 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 150000003130 pregnenes Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- INLFWQCRAJUDCR-LYLBMTSKSA-N spirostane group Chemical class [C@@H]12C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]1(C)CC[C@H]1[C@H]2CCC2CCCC[C@]12C INLFWQCRAJUDCR-LYLBMTSKSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003434 stigmastanes Chemical class 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- This invention is concerned with improvements in or relating to the preparation of steroid derivatives and more particularly with the introduction of oxygen functions into steroid molecules.
- An important characteristic of many pharmacologically-active steroids is the presence of an oxygen function, e.g. a keto or a hydroxy group, at one or more positions of the molecule, particularly at the 3-, 11-, 17- and/or 20-positions, and hence in work on the synthesis of such compounds it is desirable to have available a method of oxygenation which is convenient to use and in general gives rise to well defined products in reasonable yield.
- an oxygen function e.g. a keto or a hydroxy group
- the present invention provides a new method of introducing an oxygen function into certain steroid molecules which method has various advantageous features.
- Our invention is based upon the discovery that steroid enols can be reacted with oxygen to introduce a hydroperoxy group, frequently in good yield.
- the resulting hydroperoxide may be stable in which case it can be isolated and converted to another oxygen function, or it may spontaneously decompose, in general with formation of. an oxo group. Whether or not the hydroperoxide is isolated the process is simple to carry out and the yields are often good compared with other methods of introducing oxygen functions.
- the hydroperoxide is in general only stable when the carbon atom to which it is attached is tertiary and thus for example secondary hydroperoxides in general decompose to the corresponding ketone.
- a 3- keto steroid gives the 2,3-diketone without isolation of the intermediate hydroperoxide.
- a lZ-ketone gives the 11,12-diketone.
- a process for the introduction of an oxygen function into a steroid molecule which comprises oxygenating a steroid 2 having at least one enol group, nuclear or extra-nuclear, with molecular oxygen to form a hydroperoxy group on said steroid, which hydroperoxy group may then, depending on its stability, either spontaneously decompose to an oxo group, or, if desired, be reduced to another oxygen function eg a hydroxy group.
- the hydroperoxide group will be formed at a nuclear carbon atom adjacent to the hydroxy group of said enol group but in the case of enols derived from u: B-unsaturated ketones however the hydroperoxide may appear at the 'y-position.
- the enol steroids used in accordance with the invention may be obtained by enolisation of the corresponding keto steroid which of course results in the formation of a mixture of tautomers. If the enolising agent is weak in action then the concentration of enol will be low. This should be avoided since if the concentration of enol is too low it may not be possible to oxygen-ate the steroid or, alternatively, only low-yields of the desired endproduct may be obtained. Consequently it is desirable to produce as high a concentration of enol as possible and this is preferably effected by using a solution of a strong base in a suitable solvent, the latter in turn being one which will dissolve the keto-steroid.
- strong bases which can be used include particularly alkali metal (eg sodium or potassium) alkoxides of tertiary aliphatic alcohols e.g. tertiary butanol or tertiary amyl alcohol.
- the liquid medium employed will depend to some extent upon the nature of the base used but should be substantially anhydrous, since water in quite small amounts, e.g. 1%, can deleteriously influence the reaction leading to poor yields.
- the base itself is in general best used in excess over the steroid e.g. in an amount of 8-20 equivalents of the steroid.
- a convenient liquid medium is an alcohol especially the alcohol from which the alkoxide is derived. Particularly satisfactory are combinations of tertiary aliphatic alcohols together with their alkoxides.
- the alkali metal salt of the enolate may precipitate in the solvent used, thus preventing or hindering oxygenation.
- the oxygenation may be carried out by agitating. a solution of the steroid in the basic enolising medium with oxygen, if desired under pressure.
- the course of the reaction is readily followed by measuring the volume of oxygen absorbed.
- the reaction tends to be very fast and it. may be found that it will be complete in 10 minutes or. less. In other cases the reaction may take upwards of an hour.
- the speed of reaction would appear to be very dependant upon the structure of the compound particularly in ring C.
- we found that an ll-ketone reacted considerably more slowly than a M -compound, and that a compound with a saturated, unsubstituted ring C reacted more slowly still.
- the reaction is also affected by configuration of neighbouring groups.
- the rate of reaction is influenced if there is a l6-alkyl substituent.
- the alkyl substituent' has the p-configuration the reaction would appear to be completed more quickly than if the alkyl group has: the occonfiguration.
- the hydroperoxide formed may not be very stable in the basic enolising medium and it is desirable to keep the reaction time to a minimum if it is desired to isolate the hydroperoxide.
- the rate of oxygenation is influenced by the concentration of base in the enolising medium and preliminary trial with the desired basic enolising medium will indicate the most suitable concentration of base to give a high rate of oxygenation.
- the oxygenation is conveniently effected at or around ambient temperature but temperatures varying from to 35 C. maybe employed, if desired, At temperatures below ambient temperature however, the yield obtained may be lower.
- this may be efiected in any convenient manner e.g. by making the reaction mixture slightly acid (e.g. with acetic acid) and then precipitating the hydroperoxide with water or extracting it with an organic solvent and evaporating to dryness. To avoid decomposition during evaporation it may be advisable to employ a temperature not exceeding about 50 C.
- the hydroperoxide may be converted to the corresponding hydroxyl compound by reduction e.g. by catalytic hydrogenation or by a chemical reducing agent e.g. zinc in acetic acid, potassium iodide in acetic acid, or sodium sulphite.
- the reducing conditions should however be chosen so that the structure of the steroid is otherwise unaffected, unless by intention, and this may preclude the use of strong acids and strong bases particularly with 17a-hydroxy-20-keto steroids.
- a suitable catalyst is palladium, preferably on an inert carrier e.g. charcoal.
- the bydrogenation may be effected in a solvent such as ethanol, ethyl acetate, dioxan, tetrahydrofuran, etc.
- the process according to the invention is of particular value in that it provides a new and simple method of in troducing a 17a-hydroxy group into 20-keto steroids (in their enolic form), and in particular into 20-keto steroids having a l6fi-alkyl, particularly a 16/3-methyl, substituent.
- l6a-alkyl substituents there appear to be difficulties in the use of l6a-alkyl substituents.
- the process according to the invention is also of particular value in the introduction of a l7a-hydroxy group into 20-keto steroids containing a 9,11-double bond since, in general, it is not necessary to protect the latter during oxygenation. This is in contrast to the conventional method of Gallagher (Fieser and Fieser, Steroids, Reinhold Publishing Corp., New York, 1959, pp. 653-656).
- keto steroids which can be used with advantage in the process according to the invention are 12-.keto steroids e.g. hecogenin and botogenin and their esters. Oxygenation of such steroids by the process according to the invention leads to 11:12-diketones, which can be used as intermediates for the synthesis of pharmacologically active steroids having an oxygen function at the ll-position e.g. cortisone or prednisolone.
- the process according to the invention has also been found to be useful for the introduction of a a-hydroxy group into a 6-keto steroid.
- the process according to the invention is therefore a highly useful method for the introduction of oxygen functions into various positions of a steroid molecule and is applicable to pregnanes, spirostanes, oestranes, androstanes, cholanes, cholestanes, ergostanes, lanostanes and stigmastanes (in each case the steroid may be Socor 55-) together with their various unsaturated derivatives e.g. pregnenes, pregnadienes, etc. and homo and nor derivatives having appropriately positioned enol groups.
- steroid molecules containing two or more keto groups it is possible by selective protection e.g. by ketalisation, formation of enol ethers etc. to oxygenate at a posi tion adjacent to one of the keto groups. Where it is desired to leave the resulting hydroperoxide group intact the protecting group must be removable under mild conditions. Alternatively, Where one keto group is more reactive than others selective oxygenation is possible.
- hydroperoxy compounds obtained by the process according to the invention are new and may be used as intermediates in the manufacture of pharmacologically active compounds or may themselves possess pharmacological action.
- important new compounds according to the invention are steroids having a hydroperoxy group attached to a tertiary carbon atom in a a-position to a keto group e.g. having a Hot-hydroperoxy group and a 20-ket0 group with or without a l6B-methyl group.
- Compounds having pharmacological action include steroids of the pregnane (50c or 55) series having a 20- keto group, a 17-hydroperoxy group and a 3-keto or 3-hydroxy group (or an etherified or esterified hydroxy group or an enolised keto group) with or without one or more double bonds in the ring.
- steroids of the pregnane (50c or 55) series having a 20- keto group, a 17-hydroperoxy group and a 3-keto or 3-hydroxy group (or an etherified or esterified hydroxy group or an enolised keto group) with or without one or more double bonds in the ring.
- 3fl-hydroxy- 17a-hydroperoxy-Sa-pregnan-ZO-One is an active progestational compound as is also, although to a lesser extent, the corresponding 3a-hydroxy-55-compound.
- Other compounds having progestational activity include l7a-hydroperoxy progesterone and its 3-enol
- EXAMPLE 3 (a) Hydroperoxidation of 3fi-Acet0xy 16,8 Methyl-5a- Pregn-9(11)-En-20-One Using Potassium t-Butoxide in t-Butanol (b) 318,1 7u-Dihydr0xy-1 6,8-Methyl-5a-Pregn-9 (11 -En- ZO-One Palladium-on-charcoal 300 mg), suspended in ethanol ml.), was hydrogenated at ordinary temperature and pressure.
- the acetate has EXAMPLE 7 (i) 3,3-Hydroxy-1 6.-Methyl-5a-Pregna-9(11 ,1 6-Dien- ZO-One 3fi-acetoxy-16-methyl-5a-pregna-9(1 1 ,16-dien-20 one (10 g.) was dissolved in methylene chloride (60 ml.) and added to methanol (700 ml.) containing perchloric acid (20 ml., 60% w./w.). The solution was allowed to stand overnight at room temperature, poured into water and the white solid was filtered off and dried.
- EXAMPLE 8 (a) 3 8-11 cetoxy-I 7a-Hydr0peroxy-1 dfi-Mezfhyl-Soc-Pregn- 9 (11 -En-20-One 3 3-acetoxy-16B-methyl-5a-pregn-9 11 -en-20-one (250 mg.) in t-butyl alcohol (5 ml.), was added to a solution of sodium t-but-oxide (250 mg. sodium in 25 ml. t-butyl alcohol) and the solution was shaken with oxygen for minutes, during which time about one molecule of oxygen was absorbed.
- EXAMPLE 10 (i) 1 7a-Hydr0peroxy-3a-Hydroxy-5B-Pregnane-11 ,20- Dione (a) 3or-acetoxy-5fl-pregnane-11,20-dione ,(1 g.), dissolved in t-butyl alcohol (10 ml.), was added to a solution of potassium t-butoxide (2g. potassium dissolved in 40 ml. of t-butyl alcohol) and the solution was shakenwith oxygen for 25 minutes; after 4 minutes 1 moleculeof gas had been absorbed.
- EXAMPLE 12 (a) 17a-Hydroperoxy-3a-Hydroxy-Sfi-Pregnan-ZO-One 3a-hydroxy-5/8-pregnan-20-one (2 g.), dissolved in t-butyl alcohol (20 ml.), was added to a solution of potassium t-butoxide (4 g. potassium dissolved in 80 ml. t-butyl alcohol) and the solution was shaken with oxygen for 45 mins.; 1 molecule of oxygen was absorbed in about 35 mins.
- EXAMPLE 13 (a) 3-Eth0xy-17a-Hydroperoxypregna-3,5-Dien-ZO-One Progesterone 3-enol ethyl ether (1.8 g.) was added to a solution of potassium t-butoxide (2 g. potassium dissolved in 50 ml. t-butyl alcohol) and the solution was shaken with oxygen for 30 mins., during which time 1 mol. of oxygen was absorbed. The solution was poured into water, extracted with ethyl acetate, washed with water and dried for a short time over MgSO Evaporation of the solution to a small volume under reduced pressure at about 40 C. gave a white solid (900 mg), M.P. 130137.
- EXAMPLE 14 1 7a-H ydroperoxy progesterone 3-ethoxy-17u-hydroperoxypregna-3,5-dien-20-one (500 mg.) was dissolved by warming in methanol (25 ml.) and acetic acid (25 ml.), the solution was cooled to room temperature and the reaction was followed by change in rotation; the rotation was constant after about 2 hours. After a further 30 minutes, the reaction mixture was poured into water and the white solid was filtered oil; crystallisation from aqueous methanol gave 17u-hydroperoxyprogesterone (348 mg.; 75%), M.P. 186189 (decomp.), [a] +116 (c., 0.5 in MeOH), A max. 238- 239 III/1.,
- EXAMPLE 15 (a) 5 u-Hydroperoxy313-Hydroxycholestan-fi-One 3fi-hydroxycholestan-6-one (0.5 g.), dissolved in t-butyl alcohol (10 ml.), was added to a solution of potassium t-butoxide (1.5 g. potassium dissolved in 45 ml. t-butyl alcohol) and the solution was shaken with oxygen for 36 mins.; 1 molecule of oxygen was absorbed after 26 mins. The solution was poured into water (1,000 ml.) containing acetic acid (10 ml.) and extracted with methylene chloride. The extract was washed with water, dried (MgSO and evaporated to dryness.
- EXAMPLE 17 (a) 30A cetoxy-lofl-MethyIda-Pregna- 9(11),17(20)-Dien-20-Ol A solution of BB-acetoxy-l6-methyl-5et-pregna-9(11), 16-dien-20-one (100 g.) in tetrahydrofuran (1200 ml.) containing triethylamine (200 ml.) was hydrogenated in the presence of palladium-on-charcoal (10%, 8.5 g.); 6.5 l. of hydrogen were absorbed during 9 minutes. The solution was filtered and evaporated to dryness without excessive heating.
- a process for the introduction of an oxygen function into at least one of the 2-, 5-, 11- and l7-positions of a steroid molecule containing an enol group which comprises reacting the steroid with molecular oxygen to yield said oxygen function on the carbon atom of said enol group adjacent to the carbon atom to which the hydroxy group of said enol group is attached, said oxygen function being a hydroperoxy group when said adjacent carbon atom is tertiary and an oxo group formed by spontaneous decomposition of a hydroperoxy group when said adjacent carbon atom is secondary.
Description
United States PatentOfitice 3,056,809 Patented Oct. 2, 1962 company No Drawing. Filed Nov. 4, 1960, Ser. No. 66341 Claims priority, application Great Britain Nov. 6, 1959 Claims. (Cl. 260-37.4)
This invention is concerned with improvements in or relating to the preparation of steroid derivatives and more particularly with the introduction of oxygen functions into steroid molecules.
An important characteristic of many pharmacologically-active steroids is the presence of an oxygen function, e.g. a keto or a hydroxy group, at one or more positions of the molecule, particularly at the 3-, 11-, 17- and/or 20-positions, and hence in work on the synthesis of such compounds it is desirable to have available a method of oxygenation which is convenient to use and in general gives rise to well defined products in reasonable yield. Various methods, both chemical and micro-biological, have been proposed for the introduction of oxygen functions into steroid molecules but frequently such methods suffer from disadvantages for example requiring several separate stages and/or giving poor yield. For example, in the manufacture of adreno-cortical steroids the intermediates used are invariably lacking in a 17a-hydroxyl group and the introduction of this group has been the subject of extensive study and research. The methods so far evolved require multi-stage reactions which naturally involve concomitant loss in yield at each stage. Although some of the methods proposed have been applied on an industrial scale and the desired oxygenated steroids have been obtained in goo-d yield there still remains a desire for methods which are more direct or are otherwise more convenient. There is, for example, a need for a more selective method of hydroxylation at C(17) since existing methods sometimes give rise to difficulty because of interference by other groups or simultaneous reaction of other groups, e.g. a 9,1 l-double bond, with the reagents used.
The present invention provides a new method of introducing an oxygen function into certain steroid molecules which method has various advantageous features. Our invention is based upon the discovery that steroid enols can be reacted with oxygen to introduce a hydroperoxy group, frequently in good yield. The resulting hydroperoxide may be stable in which case it can be isolated and converted to another oxygen function, or it may spontaneously decompose, in general with formation of. an oxo group. Whether or not the hydroperoxide is isolated the process is simple to carry out and the yields are often good compared with other methods of introducing oxygen functions.
The hydroperoxide is in general only stable when the carbon atom to which it is attached is tertiary and thus for example secondary hydroperoxides in general decompose to the corresponding ketone. For example, a 3- keto steroid gives the 2,3-diketone without isolation of the intermediate hydroperoxide. Similarly, a lZ-ketone gives the 11,12-diketone.
It is of course not necessary to convert the hydroperoxy group to a hydroxyl group since one may use the former as a basis for other transformations.
According to the invention, therefore, there is provided a process for the introduction of an oxygen function into a steroid molecule which comprises oxygenating a steroid 2 having at least one enol group, nuclear or extra-nuclear, with molecular oxygen to form a hydroperoxy group on said steroid, which hydroperoxy group may then, depending on its stability, either spontaneously decompose to an oxo group, or, if desired, be reduced to another oxygen function eg a hydroxy group.
Generally speaking the hydroperoxide group will be formed at a nuclear carbon atom adjacent to the hydroxy group of said enol group but in the case of enols derived from u: B-unsaturated ketones however the hydroperoxide may appear at the 'y-position.
The enol steroids used in accordance with the invention may be obtained by enolisation of the corresponding keto steroid which of course results in the formation of a mixture of tautomers. If the enolising agent is weak in action then the concentration of enol will be low. This should be avoided since if the concentration of enol is too low it may not be possible to oxygen-ate the steroid or, alternatively, only low-yields of the desired endproduct may be obtained. Consequently it is desirable to produce as high a concentration of enol as possible and this is preferably effected by using a solution of a strong base in a suitable solvent, the latter in turn being one which will dissolve the keto-steroid.
For the purpose of the invention examples of strong bases which can be used include particularly alkali metal (eg sodium or potassium) alkoxides of tertiary aliphatic alcohols e.g. tertiary butanol or tertiary amyl alcohol. The liquid medium employed will depend to some extent upon the nature of the base used but should be substantially anhydrous, since water in quite small amounts, e.g. 1%, can deleteriously influence the reaction leading to poor yields. The base itself is in general best used in excess over the steroid e.g. in an amount of 8-20 equivalents of the steroid.
Where the basic substance is an alkoxide a convenient liquid medium is an alcohol especially the alcohol from which the alkoxide is derived. Particularly satisfactory are combinations of tertiary aliphatic alcohols together with their alkoxides.
With certain bases, which are themselves strong, e.g. alkali metal hydrides, alkali metal amides, and hindered alkali metal alkyl derivatives e.g. sodium triphenyl methyl, the alkali metal salt of the enolate may precipitate in the solvent used, thus preventing or hindering oxygenation. In general it is desirable to effect oxygenation under homogeneous conditions and thus where precipitation occurs it may be necessary to use other solvents e.g. liquid ammonia to ensure single phase conditions.
The oxygenation may be carried out by agitating. a solution of the steroid in the basic enolising medium with oxygen, if desired under pressure.
The course of the reaction is readily followed by measuring the volume of oxygen absorbed. In general, it is desirable to effect the reaction as quickly as possible, particularly in the presence of an enolising medium, to avoid decomposition of the end-products. In some cases the reaction tends to be very fast and it. may be found that it will be complete in 10 minutes or. less. In other cases the reaction may take upwards of an hour. The speed of reaction would appear to be very dependant upon the structure of the compound particularly in ring C. Thus, we found that an ll-ketone reacted considerably more slowly than a M -compound, and that a compound with a saturated, unsubstituted ring C reacted more slowly still. The reaction is also affected by configuration of neighbouring groups. For example, in: the introduction of an oxygen function at C(17) in ZO-keto steroids the rate of reaction is influenced if there is a l6-alkyl substituent. Thus if the alkyl substituent' has the p-configuration the reaction would appear to be completed more quickly than if the alkyl group has: the occonfiguration. The hydroperoxide formed may not be very stable in the basic enolising medium and it is desirable to keep the reaction time to a minimum if it is desired to isolate the hydroperoxide.
The rate of oxygenation is influenced by the concentration of base in the enolising medium and preliminary trial with the desired basic enolising medium will indicate the most suitable concentration of base to give a high rate of oxygenation.
The oxygenation is conveniently effected at or around ambient temperature but temperatures varying from to 35 C. maybe employed, if desired, At temperatures below ambient temperature however, the yield obtained may be lower.
Where it is possible to isolate the hydroperoxide this may be efiected in any convenient manner e.g. by making the reaction mixture slightly acid (e.g. with acetic acid) and then precipitating the hydroperoxide with water or extracting it with an organic solvent and evaporating to dryness. To avoid decomposition during evaporation it may be advisable to employ a temperature not exceeding about 50 C.
The hydroperoxide may be converted to the corresponding hydroxyl compound by reduction e.g. by catalytic hydrogenation or by a chemical reducing agent e.g. zinc in acetic acid, potassium iodide in acetic acid, or sodium sulphite. The reducing conditions should however be chosen so that the structure of the steroid is otherwise unaffected, unless by intention, and this may preclude the use of strong acids and strong bases particularly with 17a-hydroxy-20-keto steroids. Where catalytic hydrogenation is employed, a suitable catalyst is palladium, preferably on an inert carrier e.g. charcoal. The bydrogenation may be effected in a solvent such as ethanol, ethyl acetate, dioxan, tetrahydrofuran, etc.
The process according to the invention is of particular value in that it provides a new and simple method of in troducing a 17a-hydroxy group into 20-keto steroids (in their enolic form), and in particular into 20-keto steroids having a l6fi-alkyl, particularly a 16/3-methyl, substituent. For reasons explained above, there appear to be difficulties in the use of l6a-alkyl substituents.
The process according to the invention is also of particular value in the introduction of a l7a-hydroxy group into 20-keto steroids containing a 9,11-double bond since, in general, it is not necessary to protect the latter during oxygenation. This is in contrast to the conventional method of Gallagher (Fieser and Fieser, Steroids, Reinhold Publishing Corp., New York, 1959, pp. 653-656).
Another group of keto steroids which can be used with advantage in the process according to the invention are 12-.keto steroids e.g. hecogenin and botogenin and their esters. Oxygenation of such steroids by the process according to the invention leads to 11:12-diketones, which can be used as intermediates for the synthesis of pharmacologically active steroids having an oxygen function at the ll-position e.g. cortisone or prednisolone.
The process according to the invention has also been found to be useful for the introduction of a a-hydroxy group into a 6-keto steroid.
It would appear that the process according to the invention may possess a degree of stereo-specificity depending on the precise structure of the starting material. Thus, only one isomer was obtained on oxygenating enolic products of -ketones and 6-ketones, namely the the isomer having the OL-CODfigIlI'HtlOH.
The process according to the invention is therefore a highly useful method for the introduction of oxygen functions into various positions of a steroid molecule and is applicable to pregnanes, spirostanes, oestranes, androstanes, cholanes, cholestanes, ergostanes, lanostanes and stigmastanes (in each case the steroid may be Socor 55-) together with their various unsaturated derivatives e.g. pregnenes, pregnadienes, etc. and homo and nor derivatives having appropriately positioned enol groups.
In steroid molecules containing two or more keto groups it is possible by selective protection e.g. by ketalisation, formation of enol ethers etc. to oxygenate at a posi tion adjacent to one of the keto groups. Where it is desired to leave the resulting hydroperoxide group intact the protecting group must be removable under mild conditions. Alternatively, Where one keto group is more reactive than others selective oxygenation is possible.
It should be noted that in the presence of a basic enolising medium an ester group, e.g. 3-acetoxy, in the steroid molecule is usually hydrolysed. The possibility of preventing this will depend on the speed of oxygenation. Moreover, if extermely dry conditions are used it may be possible to hinder the hydrolysis.
Whilst we normally prefer to form the steroid enol from the corresponding ketone in a basic enolising medium it should be noted that it is not essential to form the enol in this manner. Thus, we have successfully oxygenated steroid enols obtained by other means (cf. Example 16).
The hydroperoxy compounds obtained by the process according to the invention are new and may be used as intermediates in the manufacture of pharmacologically active compounds or may themselves possess pharmacological action. Thus, important new compounds according to the invention are steroids having a hydroperoxy group attached to a tertiary carbon atom in a a-position to a keto group e.g. having a Hot-hydroperoxy group and a 20-ket0 group with or without a l6B-methyl group.
Compounds having pharmacological action include steroids of the pregnane (50c or 55) series having a 20- keto group, a 17-hydroperoxy group and a 3-keto or 3-hydroxy group (or an etherified or esterified hydroxy group or an enolised keto group) with or without one or more double bonds in the ring. For example 3fl-hydroxy- 17a-hydroperoxy-Sa-pregnan-ZO-One is an active progestational compound as is also, although to a lesser extent, the corresponding 3a-hydroxy-55-compound. Other compounds having progestational activity include l7a-hydroperoxy progesterone and its 3-enol ethers.
In order that the invention may be well understood the following examples are given by way of illustration only. In these examples the temperatures were measured in degrees centigrade.
EXAMPLE 1 Hydroperoxidation of 313-14cetoxy-I6B-Methyl-5oc-Pregn-9- (1])-En-20-One Using t-Amyl Alcohol as Solvent Sodium (2 g.) was refluxed with t-amyl alcohol (240 ml.) until dissolved, and the solution was then shaken in oxygen until there was no further absorption. 3 3-acetoxy-16/3-methyl-5a-pregn-9(11)-en-20-one (2 g.) was added and the solution was shaken with oxygen for 10 minutes. Acetic acid (20 ml.) was added and the t-amyl alcohol was distilled olf at 50 under reduced pressure. Water ml.) was added and the solution was extracted with chloroform. The extract was washed with water, dried (MgSO and evaporated to dryness under reduced pressure at 40, to give a yellow solid (1.6 g.), M.P. l49l57. crystallisation from ethyl acetate gave 17ahydroperoxy-3fl-hydroxy-16 8-methyl 5a pregn 9(1l)- en-20-one (0.95 g.z49%) in two crops, M.P. 162.5-", [0:1 +67 (c., 1.0 in MeOH). (Found: C, 72.7; H, 9.5. C H O requires C, 72.9; H, 9.45%.)
EXAMPLE 2 Hydro peroxidation of 35-11cet0xy-16fi-Methyl-5a-Pregn-9- (11)-En-20-One Using t-Butyl Alcohol as solvent Sodium (5 g.) was refluxed with t-butyl alcohol (500 ml.) until dissolved, and the solution was shaken in oxygen until there was no further absorption. 3,8-acetoxy-l6fl-methyl-5a-pregn-9(1l)-en-20-one (5 g.), dissolved in t-butanol (40 ml.), was added and the solution was shaken in oxygen for 10 mins. Acetic acid (40 ml.) and water (100 ml.) were added and the t-butanol distilled off at 40 under reduced pressure. Water (200 ml.)
was added and the solution left at overnight. The white solid which formed was filtered off and dried under vacuum at 60 to give crude 17ot-hydroperoxy-35-hydroxy-l6/3-methyl-5u-pregn-9(11) en 20 one (4.9 g.), M.P. 154-158", [a1 +44 (c.=1.0 in MeOI-l). Crystallisation from ethyl acetate gave the pure hydroperoxide (2.9 g.z59.%), M.P. 162-165", [a] +67 (c.=1.0 in MeOH).
EXAMPLE 3 (a) Hydroperoxidation of 3fi-Acet0xy 16,8 Methyl-5a- Pregn-9(11)-En-20-One Using Potassium t-Butoxide in t-Butanol (b) 318,1 7u-Dihydr0xy-1 6,8-Methyl-5a-Pregn-9 (11 -En- ZO-One Palladium-on-charcoal 300 mg), suspended in ethanol ml.), was hydrogenated at ordinary temperature and pressure. 17a-hydroperoxy-3,B-hydroxy-16B- methyl-5ot-pregn-9(1l)-en-20-one (1 g.), dissolved in ethanol (30 ml.), was added and the solution was hydrogenated for mins. The catalyst was filtered off through kieselguhr, water added and the ethanol distilled off under reduced pressure. The solution was stored at 0 for 2 hours and the white solid which formed was filtered oif and dried to give crude 3fi,17a-dihydroxy-16,8- methyl-5u-pregn-9(11)-en-20-one (0.808 g.), M.P. 186- '190; +32 (c., 1.0 in dioxan). Crystallization from aqueous methanol gave 0.543 g. of crystalline mate rial, M.P. 194-198, +39 (c., 1.0 in dioxan).
EXAMPLE 4 3,8,1 7ot-Dihydroxy-l 6,8-Methyl-5a-Pregn-9 (1 1 )-En-20-One 17a-hydroperoxy-3B-hydroxy-166 methyl 50c pregn- 9(11)-en-20-one (926 mg.) was dissolved in acetic acid (80 ml.) and zinc dust (2.5 g.acid-washed) was added. The reaction mixture was shaken for 4 hours 15 mins. at room temperature. The Zinc was filtered 01f and washed with ethyl acetate, water was added to the combined filtrates and the solution was extracted with ethyl acetate. The extract was washed with sodium bicarbonate solution and water, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure to give a semi-crystalline white solid (870 mg), M.P. 194-203", [(11 +39 (c., 1.0 in dioxan). crystallisation from aqueous methanol gave 3B,17ot-dihydroxy-16(3- give a semi-crystallihne white solid (870 mg.), M.P. crops, M.P. 199-204, [ab +39 (c., 1.0 in dioxan).
EXAMPLE 5 Cholestanone (100 mg.) was added to 1 N-potassiurn -tert-butoxide in tert-butanol (10 ml.) and the mixture was shaken with oxygen. One mole of oxygen was absorbed in 15-20 minutes and the solution became strongly yellow. An equal volume of water was then added, the mixture was acidified with 6 N-HCl and then extracted with ether. The ether extract was washed with water, extracted with aqueous sodium bicarbonate solution, washed with water again and evaporated to dryness leaving cholestan-2,3-dione. Yield, 60%, as estimated by U.V. spectrum. The product was crystallised from aqueous ethanol to give crystals M.P. 140-144, acetate :130-133".
6 EXAMPLE 6 The procedure of Example 5 was repeated using lanost- 8-en-3-one in place of cholestanone. Lanost-8-en-2,3- dione was obtained in 75% yield. On crystallisation from diethyl ether/abs. ethanol crystals were obtained M.P. 155157, [a] =+48 (acetone). The acetate has EXAMPLE 7 (i) 3,3-Hydroxy-1 6.-Methyl-5a-Pregna-9(11 ,1 6-Dien- ZO-One 3fi-acetoxy-16-methyl-5a-pregna-9(1 1 ,16-dien-20 one (10 g.) was dissolved in methylene chloride (60 ml.) and added to methanol (700 ml.) containing perchloric acid (20 ml., 60% w./w.). The solution was allowed to stand overnight at room temperature, poured into water and the white solid was filtered off and dried. Crystallization from methanol gave BB-hydroxy-lG-methyLSOt-pregna-9(11),16-dien-20-one in three crops (7.5 g., M.P. 192194, [al +59 (c., 1.0 in CHCl A purified sample had M.P. 198-199", [ed +59 (c., 1.0 in CHCl (Found: C, 80.4; H, 9.7. C H O requires C, 80.4; H, 9.8%.)
(ii) 3 fl-H ya'roxy-l 6fi-Methyl-5a-Pregn-9 (1 1 -En-20-One Palladium-on-charcoal (10%; 0.75 g.), suspended in tetrahydrofuran (80 ml.), containing triethylamine (10 ml.), was hydrogenated at room temperature and pressure. 3B-hydroxy-16-methyl-5a-pregna-9(11) ,16-dien-20 one (5 g.), dissolved in tetrahydrofuran (20 ml.), was added and the solution was hydrogenated until no further absorption occurred and 1.07 mols of hydrogen had been taken up (15 min). The catalyst was filtered off through kieselguhr and the filtrate was poured into Water and extracted with ethyl acetate. The extract was washed with 2 N-hydrochloric acid, saturated aqueous sodium bicarbonate, and water, dried over magnesium sulphate, filtered, and evaporated to dryness under reduced pressure. crystallisation of the residue from methanol gave 3,8- hydroxy-l6B-methyl-5a-pregn-9(11)-en-20 one (3.6 g., 72%), M.P. 165-168, [a] +38 (c., 1.0 in chloroform). (Found: C, 79.95; H, 10.4. C I-1 0 requires C, 79.7; H, 10.45%.)
of potassium t-butoxide (1.5 g. potassium in 45 ml. t-
butyl alcohol) and the solution was shaken with oxygen for 4 minutes, during which time 1 molecule of gas was absorbed. Isolation as in Example 3(a) and crystallisation from aqueous methanol gave 17a-hydroperoxy-3B- hydroxy-l6B-methyl-5ot-pregn-9(11)-en-20 one (50%), M.P.161-163 (decomp.), [otl +67 (c.,1.0 in MeOH).
(1)) WITH POTASSIUM t-BUTOXIDE IN t-BUTYL ALCOHOL AT 3 ATMOSPHERES PRESSURE Potassium (1.5 g.) was dissolved in t-butyl alcohol (45 ml.) and transferred to the pressure bottle of a hydrogenator. The steroid (0.5 g.) was dissolved in t-butyl alcohol (5 ml.) and sealed in a thin glass bulb, which was also placed in the pressure bottle. The bottle was evacuated and filled with oxygen at a pressure of 3 atmospheres. The bottle was shaken mechanically, when the bulb containing the. steroid was broken. The oxygenation was carried out for a further 5 minutes, and the solution was poured into water containing acetic. acid (5 ml); the white solid (550 mg.) was filtered off and dried; M.P. -158", [a] '+47 (c., 1.0 in MeOH), peroxide content 7 2%..
7 (iv) 3 3,1 7 oz-D ihydroxy-I 6 ,B-M ethyla-Pregn-9 1 1 -En- 20-One 17a-hydroperoxy-3fi-hydroxy-1Gp methyI-Sa-pregn 9 (l1)-en-20-one (250 mg.) was disoslved in ethanol (5 ml.), and acetic acid (5 ml.) and zinc dust (0.75 g.) were added. The reduction was carried out as in Example 4 to give material (225 mg), M.P. 190-195", [a1 +38 (c., 1.0 in dioxan).
EXAMPLE 8 (a) 3 8-11 cetoxy-I 7a-Hydr0peroxy-1 dfi-Mezfhyl-Soc-Pregn- 9 (11 -En-20-One 3 3-acetoxy-16B-methyl-5a-pregn-9 11 -en-20-one (250 mg.) in t-butyl alcohol (5 ml.), was added to a solution of sodium t-but-oxide (250 mg. sodium in 25 ml. t-butyl alcohol) and the solution was shaken with oxygen for minutes, during which time about one molecule of oxygen was absorbed. Isolation as in Example 3(a) and crystallisation from aqueous methanol gave 3/3-acetoxy-l7a-hydroperoxy-l6fl-methyl-5a-pregn-9(1l)-en-20 one, M.P. 156-158", [(11 +57 (c., 1.0 in MeOH). The analytical specimen had M.P. 161-164 (decomp.), [a] +57 (c., 1.0 in MeOH). (Found: C, 71.1; H, 9.1. C H O requires C, 71.25; H, 9.0%.)
3fl-Acetoxy-17u-hydroperoxy-l6B-rnethyl-5a-pregn 9- (ll)-en-20-one (100 mg.) was dissolved in acetic acid (10 ml.), and zinc dust (400 mg.; acid-washed) was added. The reaction mixture was shaken at room temperature for 4 hours, the zinc was filtered oil and the precipitate was washed with ethyl acetate. The combined filtrate and washings were diluted with water, extracted with ethyl acetate, the extract washed with sodium bicarbonate solution and water, dried over magnesium sulphate, filtered and evaporated to dryness, to give a white solid (110 mg), M.P. 158-160. Crystallisation from aqueous methanol gave 3 3 acetoxy-l7a-hydroxy-l6B-methy1-5apregn-9(1l)-en-20-one (63%), M.P. 163-166, [011 +32 (c., 1.0 in dioxan).
EXAMPLE 9 (i) J 7u-Hydr0p eroxy-jfi-Hydroxy-5a-Pregnane-1 1 ,20- Diane (a) 3,8-acetoxy-5a-pregnane-11,20 dione (1 g.), dissolved in t-butyl alcohol (10 ml.), was added to a solution of potassium t-butoxide, prepared from potassium (2 g.) and t-butyl alcohol (45 ml.), and the solution was shaken with oxygen for 20 mins.; absorption of 1 molecule of gas had occurred after about 10 mins. Isolation as in Example 3(a) and crystallisation from ethyl acetate gave 17a-hydroperoxy 3fi-hydroxy-Su-pregnane-I1,20- dione (54%), M.P. 161-163" (decomp.), [ab +71 (c., 1.0 in MeOH). (Found: C, 69.0; H, 8.9. C H O requires C, 69.2; H, 8.85%.)
(b) Hydroperoxidation of 3fl-hydroxy-5a-pregnane-ll, 20- dione under similar conditions to those described in (a), but decreasing the total reaction time to 10 minutes gave l7a-hydroperoxy-3j3-hydroxy-5u-pregnane 11,20- dione in 51% yield.
(ii) 36,] 7a-DihydrOxy-Su-Pregnane-I1,20-Di0ne 17a-hydroperoxy-3p-hydroxy-5a-pregnane-11,20 dione (100 mg.) in acetic acid (30 ml.) was reduced with zinc (400 mg.) and the product isolated as in Example 4. crystallisation from aqueous methanol gave 3,6,17a-dihydroxy-5wpregnane-11,20-dione (78%), M.P. 284-287, [ab +65 (c., 1.0 in dioxan).
EXAMPLE 10 (i) 1 7a-Hydr0peroxy-3a-Hydroxy-5B-Pregnane-11 ,20- Dione (a) 3or-acetoxy-5fl-pregnane-11,20-dione ,(1 g.), dissolved in t-butyl alcohol (10 ml.), was added to a solution of potassium t-butoxide (2g. potassium dissolved in 40 ml. of t-butyl alcohol) and the solution was shakenwith oxygen for 25 minutes; after 4 minutes 1 moleculeof gas had been absorbed. Isolation as in Example 3(a) and crystallisation from ethyl acetate gave 17a-hydroperoxy-3a-hydroxy-5fi-pregnane-l1,20-dione (57% M.P. 158-160 (decomp.), [ab (c., 1.0 in MeOH). (Found: C, 69.0; H, 8.8. C H O requires C, 69.2; H, 8.85
(b) Hydroperoxidation of 3m-hydroxy-5/8-pregnane 11,20-dione under similar conditions but decreasing the total reaction time to 10 minutes (when absorption of oxygen was complete), gave l7u-hydroperoxy-3m-hydroxy-SB-pregnane-l1,20-dione in 33% yield.
(ii) 3a,] 7ot-Dihydroxy-SB-Pregnane-l1,20-Di0ne 17c: hydroperoxy 30c hydroxy 5,8 pregnancl1,20-dione (84 mg.) in acetic acid (25 ml.) was reduced with zinc (500 mg.) and the product isolated as in Example 4. Crystallisation from aqueous methanol gave 3a,l7a-dihydroxy-Sfi-pregnane-11,20-dione (70%), M.P. 203-208, [ot] +66 (c., 1.0 in acetone).
EXAMPLE 11 (i) I 7a-Hydroperoxy-3fl-Hydr0xy-5a-Pregnan-20-One (a) 3,B-acetoxy-Saregnan-ZO-one (1 g.), dissolved in t-butyl alcohol (10 ml.), was added to a solution of potassium t-butoxide (2 g. potassium dissolved in 40 ml. t-butyl alcohol) and the solution was shaken with oxygen for 38 mins.; 1 molecule of gas was absorbed after about 14 mins. Isolation as in Example 3(a) and crystallisation from methanol gave 17a-hydroperoxy-3fi-hydroxy-Sapregnan-ZO-one (35%), M.P. 169-172 (decomp.), [0:]D +54 (c., 0.5 in MeOH). (Found: C, 71.6; H, 10.05. C21H3404 requires C, H, 9.8%-)
(b) 3,B-hydroxy-5a-pregnan-20-one (5 g.), dissolved in t-butyl alcohol (50 ml.), was added to a solution of potassium t-butoxide (5 g. potassium dissolved in 75 ml. t-butyl alcohol) and the solution was oxygenated for 45 mins. and worked up as described previously to give crude 17ahydroperoxy-3fi-hydroxy-5a-pregnan-ZO-One (5 g.). Trituration with a small quantity of ether gave 3.5 g. of material with M.P. 160-162; crystallisation from ethanol then gave l7a-hydroperoxy-3 B-hydroxy-5a-pregnan-20- one in 44% yield, M.P. 172-174, [1x1 +54 (c., 0.5 in MeOH).
(ii) 3 18,1 7u-Dihydroxy-Sa-Pregnan-ZO-One 17a-hydroperoxy-3B-hydroxy-5a-pregnan 20 one (65 mg.) in acetic acid (25 ml.) was reduced with zinc (500 mg.) and the product isolated as in Example 4. Crystallisation from ethyl acetate gave 3;8,17a-dihydroxy-5apregnan-ZO-one (59%), M.P. 251-256, [ab +35 (c., 1.0 in EtOH).
EXAMPLE 12 (a) 17a-Hydroperoxy-3a-Hydroxy-Sfi-Pregnan-ZO-One 3a-hydroxy-5/8-pregnan-20-one (2 g.), dissolved in t-butyl alcohol (20 ml.), was added to a solution of potassium t-butoxide (4 g. potassium dissolved in 80 ml. t-butyl alcohol) and the solution was shaken with oxygen for 45 mins.; 1 molecule of oxygen was absorbed in about 35 mins. Isolation as in Example 3(a) and crystallisation from ethyl acetate gave 17oc-hYdI0P6IOXY-3oc-hYCll'OXY-SB- pregnan-ZO-one (1.0 g., 46% M.P. 162-l63 (decomp.), [0:1 +64 (c., 1.0 in MeOH).
(b) 3 0a,] 7 a-D ihydroxy-S B-Pregnah-ZO-One 17a-hydroperoxy-3 a-hydrQXy-SB-pregnan 20 one mg.) was dissolved in acetic acid (25 ml.), zinc (300 mg.) was added and the solution was shaken for 4 hours. The zinc was filtered oil and the precipitate washed with chloroform. The combined filtrate and washings were washed with sodium bicarbonate solution and water, dried (MgSO and evaporated to dryness, to give a white 9 solid (89 mg). Crystallisation from aqueous methanol gave 3a,17a-dihydroxy-5fi-pregnan-20-one (62%), M.P. 213-216", [aJ +63 (c., 1.0 in ethanol).
EXAMPLE 13 (a) 3-Eth0xy-17a-Hydroperoxypregna-3,5-Dien-ZO-One Progesterone 3-enol ethyl ether (1.8 g.) was added to a solution of potassium t-butoxide (2 g. potassium dissolved in 50 ml. t-butyl alcohol) and the solution was shaken with oxygen for 30 mins., during which time 1 mol. of oxygen was absorbed. The solution was poured into water, extracted with ethyl acetate, washed with water and dried for a short time over MgSO Evaporation of the solution to a small volume under reduced pressure at about 40 C. gave a white solid (900 mg), M.P. 130137. Crystallisation from aqueous acetone gave 3-ethoxy-17ot-hydroperoxypregna-3,S-dien 20 one (590 mg; 30%), M.P. 135137, [M 84 (c., 0.5 in MeOH), 7 max. 239-240 m (Found: C, 73.5; H, 9.25. C H O requires C, 73.8; H, 9.15%.)
EXAMPLE 14 1 7a-H ydroperoxy progesterone 3-ethoxy-17u-hydroperoxypregna-3,5-dien-20-one (500 mg.) was dissolved by warming in methanol (25 ml.) and acetic acid (25 ml.), the solution was cooled to room temperature and the reaction was followed by change in rotation; the rotation was constant after about 2 hours. After a further 30 minutes, the reaction mixture was poured into water and the white solid was filtered oil; crystallisation from aqueous methanol gave 17u-hydroperoxyprogesterone (348 mg.; 75%), M.P. 186189 (decomp.), [a] +116 (c., 0.5 in MeOH), A max. 238- 239 III/1.,
(Found: C, 72.8; H, 8.7. C H O requires C, 72.8; H, 8.7%.)
EXAMPLE 15 (a) 5 u-Hydroperoxy313-Hydroxycholestan-fi-One 3fi-hydroxycholestan-6-one (0.5 g.), dissolved in t-butyl alcohol (10 ml.), was added to a solution of potassium t-butoxide (1.5 g. potassium dissolved in 45 ml. t-butyl alcohol) and the solution was shaken with oxygen for 36 mins.; 1 molecule of oxygen was absorbed after 26 mins. The solution was poured into water (1,000 ml.) containing acetic acid (10 ml.) and extracted with methylene chloride. The extract was washed with water, dried (MgSO and evaporated to dryness. The gummy residue was crystallised from ethyl acetate (charcoal) to give 5a-hydroperoxy-3fl-hydroxycholestane-6one (20%), M.P. 192-195 (decomp.), [ab 5 (c., 1.0 inMeOH). (Found: C, 74.35; H, 10.6. C27H46O4 requires C. 74.6; H, 10.7%.)
(b 3 5,5 ot-Dihydrxych0lestan-6 One ot-hydroperoxy-3fl-hydroxycholestan-6-one (25 mg.) was dissolved in acetic acid ml.) and the solution was shaken with zinc (300 mg.) for 4 hours. The zinc was filtered oil, the precipitate washed with ethyl acetate, the combined filtrates were washed with sodium bicarbonate solution and water, dried (MgSQ and evaporated to dryness to give a white solid (26 mg). Crystallisation from aqueous methanol gave 3{8,5u-dihydroxycholestan-6-one (50%), M.P. 232-234, [0th, -24 (c., 0.5 in CHCl EXAMPLE 16 Treatment of Hec genin With Oxygen in Basic Medium Hecogenin (1 g.), dissolved in t-butyl alcohol (30 ml.), was added to a solution of potassium t-butoxide (4 g. potassium in 90 ml. t-butyl alcohol) and the solution was shaken with oxygen for 3 /2 hours, during which time nearly 2 mol. of oxygen was absorbed. The solution was poured into water (1,000 ml.) containing acetic acid (10 ml.), the product was stored at 0 for 2 hours, filtered and dried. The product had M.P. 158-163", [ml -22 (c., 1.0 in CHCl The crude product (1.1 g.) was dissolved in pyridine (6 ml.) and acetic anhydride (8 ml.) was added; the solution was heated on a steam bath for 4 hours, poured onto ice and the solid filtered oif and dried. The product (0.9 g.) was dissolved in benzene and chromatographed on magnesium trisilicate g.), the column being eluted with benzene and benzene containing ethyl acetate. Crystallisation of the eluted material from ethanol, gave as 1st crop, hecogenin acetate (100 mg), M.P. 238-242, [@1 2" (c., 1.0 in CHCl Concentration of the mother liquors gave 3/3,11-diacetoxy- 5a,25D-spirost-9(11)-en-12-one (152 mg.), M.P. 187- 191, [ab +19 (c., 1.0 in CHCl A max. 243 m (Found: c, 70.15; H, 8.6. Calc. for 0 mm,: 0, 70.4; H, 8.4%.)
EXAMPLE 17 (a) 30A cetoxy-lofl-MethyIda-Pregna- 9(11),17(20)-Dien-20-Ol A solution of BB-acetoxy-l6-methyl-5et-pregna-9(11), 16-dien-20-one (100 g.) in tetrahydrofuran (1200 ml.) containing triethylamine (200 ml.) was hydrogenated in the presence of palladium-on-charcoal (10%, 8.5 g.); 6.5 l. of hydrogen were absorbed during 9 minutes. The solution was filtered and evaporated to dryness without excessive heating. The residue was suspended in acetone (200 ml.), filtered and the solid washed with acetone (3 x 50 ml.) and dried at 60 in vacuo. The enol (25.15 g.), so obtained, was purified by being suspended in acetone (500 ml.), which was then heated to reflux and cooled to room temperature. The 3fi-acetoxy-16B-methyl- 5a-pregna-9(11),17(20)-dien-20-ol was filtered, washed with acetone (200 ml.) and dried at 60 in vacuo; 20.8 g., M.P. 134-l40, [oc] +30.6 (c., 1 in CHClg). (Found: C, 77.3; H, 9.7; active H, 0.21. C H O' requires C, 77.4; H, 9.7; active H, 0.27%.)
(b) 3 B-A cetoxy-I 7a-Hydr0peroxy-1 6fi-Methyl-5a- Pregn-9 (l1 En-ZO-One 3(3 acetoxy -16B methyl 5a pregna 9(11),17(20)- dien-20-ol (2 g.) was dissolved in warm benzene (200 ml.). The solution was cooled to room temperature and shaken with oxygen until 1 molecule of the gas had been absorbed (ca. 2 minutes). Evaporation of the solution gave a white solid which, on crystallisation from aqueous methanol, yielded 3B-acetoxy-17u-hydroperoxy-16fi-methyl-5a-pregn9(1l)-en-20-one; 0.95 g., M.P. 158l60, [a] +57 (c., 1.0 in MeOH).
We claim:
1. A process for the introduction of an oxygen function into at least one of the 2-, 5-, 11- and l7-positions of a steroid molecule containing an enol group which comprises reacting the steroid with molecular oxygen to yield said oxygen function on the carbon atom of said enol group adjacent to the carbon atom to which the hydroxy group of said enol group is attached, said oxygen function being a hydroperoxy group when said adjacent carbon atom is tertiary and an oxo group formed by spontaneous decomposition of a hydroperoxy group when said adjacent carbon atom is secondary.
2. A process as claimed in claim 1 in which the oxygen is used under pressure.
3. A process as claimed in claim 1 in which the hydroperoxide is recovered by making the reaction mixture slightly acid.
4. A process as claimed in claim 1 in which the oxygen function is a hydroperoxy group which is thereafter reduced to form a hydroxyl group.
5. A process as claimed in claim 4 in which the steroid enol corresponds to a ZO-keto steroid and the process is used to introduce a 17a-hydroxy group.
6. A process as claimed in claim 5 in which the steroid enol has a 16B-alkyl substituent.
7. A process as claimed in claim 1 in which the enolic steroid is formed by enolising the corresponding keto steroid in a strongly basic enolising medium.
8. A process as claimed in claim 7 in which said medium is a solution of an alkali metal tertiary alkoxide in a tertiary alkanol.
9. A process as claimed in claim 7 in which said medium is a solution of an alkali metal tertiary alkoxide in a tertiary alkanol selected from the group consisting of tertiary butanol and tertiary amyl alcohol.
10. A process as claimed in claim 7 in which the base is used in an amount of 820 equivalents of the keto steroid.
11. 3p-hydroxy-17a-hydroperoxy-5a-pregnan-ZO-One.
13. A compound selected from the groups consisting of 17a-hydroperoxy-progesterone and its 3-lower alkyl enol others.
. 14.-A compound selected from the group consisting of a compound of the formula CH3 i 3 of hydrogen and a lower alkyl group; 17a-hydroperoxy- No references cited.
Claims (1)
1. A PROCESS FOR THE INTRODUCTION OF AN OXYGEN FUNCTION INTO AT LEAST ONE OF THE 2-, 5-, 11- AND 17-POSITIONS OF A STEROID MOLECULE CONTAINING AN ENOL GROUP WHICH COMPRISES REACTING THE STEROID WITH MOLECULAR OXYGEN TO YIELD SAID OXYGEN FUNCTION ON THE CARBON ATOM OF SAID ENOL GROUP ADJACENT TO THE CARBON ATAOM TO WHICH THE HYDROXY GROUP OF SAID ENOL GROUP IS ATTACHED, SAID OXYGEN FUNCTION BEING A HYDROPEROXY GROUP WHEN SAID ADJACENT CARBON ATOM IS TERTIARY AND AN OXO GROUP FORMED BY SPONTANEOUS DECOMPOSITION OF A HYDROPEROXY GROUP WHEN SAID ADJACENT CARBON ATOM IS SECONDARY.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3356696A (en) * | 1965-05-24 | 1967-12-05 | Schering Corp | Method for introducing an oxygen function into a steroid molecule containing a keto group |
US3372175A (en) * | 1965-11-01 | 1968-03-05 | Syntex Corp | 19-nor-14beta, 17alpha-pregnane derivatives and process |
US3372174A (en) * | 1964-07-08 | 1968-03-05 | Syntex Corp | Process for converting 17alpha-hydroperoxy-20-keto-pregnanes into the corresponding 17-keto-androstanes |
US6667410B2 (en) | 2000-09-18 | 2003-12-23 | Board Of Regents, The University Of Texas System | Conversion of α,β-unsaturated ketones and α,β-unsaturated esters into α-hydroxy ketones and α-hydroxy esters using Mn(III) catalyst, phenylsilane and dioxygen |
-
1960
- 1960-11-04 US US66941A patent/US3056809A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
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None * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3372174A (en) * | 1964-07-08 | 1968-03-05 | Syntex Corp | Process for converting 17alpha-hydroperoxy-20-keto-pregnanes into the corresponding 17-keto-androstanes |
US3356696A (en) * | 1965-05-24 | 1967-12-05 | Schering Corp | Method for introducing an oxygen function into a steroid molecule containing a keto group |
US3372175A (en) * | 1965-11-01 | 1968-03-05 | Syntex Corp | 19-nor-14beta, 17alpha-pregnane derivatives and process |
US6667410B2 (en) | 2000-09-18 | 2003-12-23 | Board Of Regents, The University Of Texas System | Conversion of α,β-unsaturated ketones and α,β-unsaturated esters into α-hydroxy ketones and α-hydroxy esters using Mn(III) catalyst, phenylsilane and dioxygen |
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